Abstract
Fear extinction is the laboratory basis of exposure therapy for anxiety disorders. Recent findings have revealed that estradiol is necessary to the consolidation of extinction memories in females. These findings are based on studies conducted using virgin rats and young women whose reproductive history is unknown. We hypothesized that motherhood, which results in extensive endocrinological, neurobiological and behavioral changes, may lead to alterations in fear extinction in females. We used a cross-species translational approach to investigate the impact of reproductive experience on fear extinction and fear relapse in female rats (n=116) and women (n=64). Although freezing during extinction recall was associated with estrous cycle phase during extinction training in virgin rats, this association was mitigated in age-matched reproductively experienced rats, even when fear extinction occurred 3 months after pups had been weaned, and even though reproductively experienced rats exhibited attenuated serum estradiol levels. In addition, although serum estradiol levels predicted extinction recall in human women with no prior reproductive experience, no such association was found in women with children. Finally, although virgin rats displayed both renewal and reinstatement after fear extinction, these common relapse phenomena were absent in rats with reproductive experience. Together, these findings suggest that reproductive experience alters the endocrine and behavioral features of fear extinction in females long after the hormonal surges of pregnancy and lactation have diminished. These results highlight the need to incorporate both hormonal and reproductive status as important factors in current models of fear extinction in females.